Nearly 60,000 new cases of non-Hodgkin's lymphoma (NHL) are diagnosed each year in the United States, and it is the fifth most common cause of cancer death. One of the major oncogenic abnormalities in NHL is its inherent resistance to apoptosis, which ultimately contributes to drug resistance and tumor progression. Until recently, most treatments for NHL have attempted to overcome apoptosis-resistance with traditional chemotherapeutic agents or radiation therapy, but these modalities adversely impact the normal tissues as well as tumor cells. In contrast, anti-CD20 monoclonal antibodies (MoAbs) such as rituximab preferentially target normal and malignant B-cells and induce cell death via a number of mechanisms including apoptosis. Unfortunately, most clinical responses to rituximab alone are partial and remission durations are typically less than 1 year. Attempts to improve the efficacy of anti-CD20 MoAbs without adding toxicity have met with limited success. Our pre-clinical data demonstrate that fenretinide, a non-toxic oral pro-apoptotic retinoid, exhibits substantial single-agent activity and can dramatically enhance the anti-tumor effect of anti-CD20 MoAbs. The objective of this research proposal is to conduct a novel phase l/ll clinical trial evaluating the ability of fenretinide to amplify responses to anti-CD20 antibody therapy without incurring significant additional toxicity. In Aim 1 we will assess the clinical activity of fenretinide alone and in combination with rituximab in patients with B-NHL using both traditional response measures as well as positron emission tomographic responses. Aim 2 will evaluate the plasma, marrow and tumor pharmacokinetics of fenretinide and retinol and correlate these findings with the dose limiting toxicities and clinical responses. Aim 3 will determine tumor-specific predictors of clinical response and elucidate the in vivo mechanisms of action by evaluating markers of proliferation, apoptosis-resistance and ex vivo apoptosis-induction measures. The results of this project will be critical to the future development of this therapy and potentially lead to a novel, practical, inexpensive, well-tolerated, oral method to optimize the efficacy of anti-CD20 therapy for B-NHL. [unreadable] [unreadable]